The present invention is directed toward selected (S)-enantiomeric methanesulfonamides characterized by a hydroxy-alkyl linkage between a tertiary amine group having a substituted side chain and a methanesulfonamide substituted phenyl, useful as Class III antiarrhythmics. These novel enantiomeric methanesulfonamides prolong the effective refractory period of the myocardium and are very potent and stable against metabolism. More importantly, these Class III antiarrhythmic compounds do not have the undesirable side effect of producing polymorphic ventricular tachycardia ("PVT").
Antiarrhythmic drugs act upon the electrophysiological properties of the myocardium and conductive tissues. Typically the rhythmic contractions of the heart are dependent upon the ability of the myocardium and conductive tissues to respond to electrical impulses. When the conductivity of the heart's muscle and conductive tissue is altered by an occlusion of an artery or disease, a life threatening cardiovascular deterioration is likely. It is therefore desirable to treat the electrophysiological properties of the myocardium and conductive tissue to restore rhythmic contractions.
One means for restoring rhythmic contraction is with an antiarrhythmic agent that selectively prolongs the action potential duration and concomitantly increases the refractory period of heart cells without significant effect on cardiac conduction. Such drugs are classified as Class III antiarrhythmic agents. Class III antiarrhythmics which have good bioavailability and which do not affect other circulatory parameters such as blood pressure and heart rate are continually being sought. The subject compounds are Class III antiarrhythmics which are suitable for the treatment of mammals suffering from arrhythmic disorders or disease.
Unfortunately, Class III antiarrhythmic agents are known to produce PVT or torsades de pointes, which is a drug-induced arrhythmia, in a percentage of patients treated with these agents. This potentially lethal arrhythmia represents a liability for this class of antiarrhythmic agents. Surprisingly, it has been discovered that the instant compounds, although potent Class III antiarrhythmics, do not cause PVT in an animal model for this arrhythmia. This is a breakthrough in preparing a Class III antiarrhythmic without the serious PVT side effect.
Bioavailability is an important characteristic of any drug. Unfortunately, with compounds similar to the subject compounds such as those disclosed in U.S. Pat. No. 5,155,268, bioavailability is hampered by a rapid metabolism of the amine side chain. The subject invention solves this problem, as previously disclosed in PCT WO 91/01299, by substituting the side chain with at least one fluorine atom to prevent rapid metabolism and thereby increase bioavailability.